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Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non-small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified. Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations. Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations. [ABSTRACT FROM AUTHOR]

Lung specimens were collected from 161 non-smoking male patients with carcinoma to determine the deposition of carbon particles and oxidative damage in lung tissues. Morphologically, carbon particles deposited in human lungs with carcinoma were similar to those of diesel exhaust like particles, and mass of particles showed a significant increase with the increasing age of the patients. An increasing age of patient with carcinomas was also associated with 8-oxodeoxy-guanosine (8-oxo-dG) formation, which was analyzed using the HPLC-electrochemical detector method. In addition, it was found that 8-oxo-dG increased in cancerous tissues rather than in non-cancerous ones. To determine whether particles in lung tissues were associated with 8-oxo-dG formation, carbon particles deposited in lung tissues were partially purified by cycling of alkali fusion with 1M KOH; mutagenic chemicals in particles were extracted and excluded by removal with an equal volume of benzene/methanol and dichloromethane. It was also found that 8-oxo-dG was formed by non-mutagenic particles, and enhanced in the in vivo test using mouse rather than in the in vitro using RAW 254.7 tissue cultured cells. The 8-oxo-dG formation in vivo was due to the fact that hydroxyl radicals might be involved with phagocytosis of non-mutagenic particles in inflammatory cells, and the mutation was induced by hydroxylation of guanine residue on DNA. These results were also demonstrated by the occurrence of alveolar macrophages and neutrophils after intratracheal instillation of particles. These observations suggest that small particles from lung cancer patients further promote oxidative damage when used to treat the mouse lung. Especially, particles from which organic chemicals were removed were highly reactive to oxidative damage and formed 8-oxo-dG. [ABSTRACT FROM AUTHOR]

The effect of genetic polymorphism of DNA repair enzyme on the DNA adduct levels was evaluated in this study. We explored the relationship between polymorphism in the nucleotide excision repair enzyme XPD and DNA adduct levels in lymphocytes. Lymphocyte DNA adducts were measured by a [sup 32]P-postlabelling method from 42 subjects. XPD ex23 genotypes were identified by the PCR-RFLP method. Subjects with the XPD ex23 heterozygous genotype (AC) showed significantly lower DNA adduct levels (0.63 ± 0.19 per 10[sup 8] nucleotides, n = 6) than those (0.92 ± 0.38, n = 36) with major homozygous genotypes (AA). This result suggests that the genotype of the repair enzyme may be one of the important determinants for DNA adduct levels. [ABSTRACT FROM AUTHOR]

We have investigated the correlation between DNA adduct levels and aryl hydrocarbon hydroxylase (AHH) activity in peripheral lymphocyte samples obtained from 42 lung cancer patients. DNA adducts and AHH activity were determined by the [sup 32] P-postlabelling technique and the fluorometric method, respectively. The mean +/- SD of DNA adduct level was 0.88 +/- 0.37 (ranged from 0.22 to 1.90) per 10[sup 8] nucleotides. The geometric means of non-induced and 3-methylcholanthrene (MC)-induced AHH activity, as well as AHH inducibility (MC-induced AHH activity/non-induced AHH activity) were 0.029, 0.228 pmol min[sup -1] 10[sup -6] cells, and 7.776, respectively. There was no statistically significant correlation between DNA adduct levels and non-induced or MC-induced AHH activity. A tendency of positive correlation was found between DNA adduct levels and AHH inducibility for the all subjects (n= 42, r= 0.25, p= 0.11). Such a positive correlation reached statistical significance in the subjects with squamous cell carcinoma (n= 13, r= 0.70, p< 0.01). In addition, similar correlation of DNA adducts with AHH inducibility was also observed in the GSTM1 present genotype (n= 17, r= 0.44, p= 0.07) and GSTP1-AA genotype (n= 29, r= 0.37, p= 0.05) individuals. These findings suggest that DNA adduct levels are mediated by CYP1A1 enzyme, and AHH inducibility may be a more relevant indicator than specific AHH activity for explaining the variation of DNA adduct levels in lymphocytes. [ABSTRACT FROM AUTHOR]